The long-term goal of our group is to identify therapeutic targets in autism spectrum disorders (ASDs) and this proposal will focus on SHANK3 where it has been shown that deletions and mutations lead to ASDs. The overall objective of the proposal is to identify therapeutic targets for SHANK3-haploinsufficiency and our central hypothesis is that haploinsufficiency of SHANK3 leads to alterations in synapse development, glutamate transmission and synaptic plasticity in vivo that lead to observable behavioral phenotypes. The rationale for this proposal is that as we begin to understand the molecular, cellular, and regional impact of SHANK3 haploinsufficiency in vivo, we will have new targets that can form the basis of novel therapies for ASDs and associated disorders. In Aim 1, we will measure excitatory synaptic function in Shank3-deficient mice by electrophysiology and synaptic biochemistry. In Aim 2, we will quantify neuronal morphology and synapse structure and density in these animals. In Aim 3, we will access social and learning and memory behaviors in the Shank3-deficient mice. In Aim 4 will assess research compounds for effects in the mice using molecular deficits in synapses (Aim 1) to define targets for experimental interventions, with electrophysiological (Aim 1), morphological (Aim 2), and behavioral changes (Aim 3) as endpoints to assess the efficacy of a given intervention. The studies are significant because they represent a first step towards ultimate therapies for SHANK3-haploinsufficiency syndromes in that they will (a) identity molecular targets for therapies and (b) define preclinical outcome measures to be used for the assessment of novel therapeutics. In addition, as SHANK3 is such a central player in the synapse, these studies will also advance our understanding of the basic neurobiology of the synapse. The studies will also provide important data on the molecular, cellular and network components that underlie cognition and social behaviors. The proposed research is innovative, in our opinion, because it for the first time makes use of Shank3-deficient mice to study Shank3 function in situ, as a model for SHANK3-haploinsufficiency. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health and to the NIH mission because the studies will lead to a molecular and systems level understanding of Shank3 function and will identify molecular targets for novel therapeutics in human SHANK3-haploinsufficiency and in autism spectrum disorders. In addition, these studies will advance our understanding of the basic neurobiology of the synapse and of brain components that underlie cognition and social behaviors.